Elsevier

The Lancet Oncology

Volume 13, Issue 1, January 2012, Pages 100-110
The Lancet Oncology

Articles
Cross-protective efficacy of HPV-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by non-vaccine oncogenic HPV types: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial

https://doi.org/10.1016/S1470-2045(11)70287-XGet rights and content

Summary

Background

We evaluated the efficacy of the human papillomavirus HPV-16/18 AS04-adjuvanted vaccine against non-vaccine oncogenic HPV types in the end-of-study analysis after 4 years of follow-up in PATRICIA (PApilloma TRIal against Cancer In young Adults).

Methods

Healthy women aged 15–25 years with no more than six lifetime sexual partners were included in PATRICIA irrespective of their baseline HPV DNA status, HPV-16 or HPV-18 serostatus, or cytology. Women were randomly assigned (1:1) to HPV-16/18 vaccine or a control hepatitis A vaccine, via an internet-based central randomisation system using a minimisation algorithm to account for age ranges and study sites. The study was double-blind. The primary endpoint of PATRICIA has been reported previously; the present analysis evaluates cross-protective vaccine efficacy against non-vaccine oncogenic HPV types in the end-of-study analysis. Analyses were done for three cohorts: the according-to-protocol cohort for efficacy (ATP-E; vaccine n=8067, control n=8047), total vaccinated HPV-naive cohort (TVC-naive; no evidence of infection with 14 oncogenic HPV types at baseline, approximating young adolescents before sexual debut; vaccine n=5824, control n=5820), and the total vaccinated cohort (TVC; all women who received at least one vaccine dose, approximating catch-up populations that include sexually active women; vaccine n=9319, control=9325). Vaccine efficacy was evaluated against 6-month persistent infection, cervical intraepithelial neoplasia grade 2 or greater (CIN2+) associated with 12 non-vaccine HPV types (individually or as composite endpoints), and CIN3+ associated with the composite of 12 non-vaccine HPV types. This study is registered with ClinicalTrials.gov, number NCT00122681.

Findings

Consistent vaccine efficacy against persistent infection and CIN2+ (with or without HPV-16/18 co-infection) was seen across cohorts for HPV-33, HPV-31, HPV-45, and HPV-51. In the most conservative analysis of vaccine efficacy against CIN2+, where all cases co-infected with HPV-16/18 were removed, vaccine efficacy was noted for HPV-33 in all cohorts, and for HPV-31 in the ATP-E and TVC-naive. Vaccine efficacy against CIN2+ associated with the composite of 12 non-vaccine HPV types (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68), with or without HPV-16/18 co-infection, was 46·8% (95% CI 30·7–59·4) in the ATP-E, 56·2% (37·2–69·9) in the TVC-naive, and 34·2% (20·4–45·8) in the TVC. Corresponding values for CIN3+ were 73·8% (48·3–87·9), 91·4% (65·0–99·0), and 47·5% (22·8–64·8).

Interpretation

Data from the end-of-study analysis of PATRICIA show cross-protective efficacy of the HPV-16/18 vaccine against four oncogenic non-vaccine HPV types—HPV-33, HPV-31, HPV-45, and HPV-51—in different trial cohorts representing diverse groups of women.

Funding

GlaxoSmithKline Biologicals.

Introduction

Infection with oncogenic human papillomavirus (HPV) types is a necessary cause of invasive cervical cancer (ICC).1, 2 Roughly 15 HPV types have been classified as oncogenic. Among these, HPV-16 and HPV-18 are the most prevalent, and cause around 70% of ICC worldwide.3 The next most prevalent oncogenic type is HPV-45.3 HPV-16 (A9 species) together with HPV-18 and HPV-45 (A7 species) cause 75% of squamous-cell carcinoma (SCC) and 94% of adenocarcinoma.3 The next five most common oncogenic HPV types are all from the A9 species (HPV-31, HPV-33, HPV-35, HPV-52, and HPV-58) and together cause another 15% of ICC.3 The remaining oncogenic HPV types individually cause a very small proportion of ICC worldwide (<2%) and include HPV-51 (A5 species), HPV-56 (A6 species), and HPV-39 and HPV-59 (A7 species).3, 4, 5 The possible carcinogenicity of HPV-66 (A6 species) is uncertain, whereas HPV-68 (A7 species) is probably oncogenic.4

Prophylactic HPV vaccines are administered in vaccination programmes targeted at young adolescent girls before sexual exposure, and in catch-up programmes for young women in some countries. Since non-vaccine HPV types account for around 30% of cervical cancers, cross-protection against these types would potentially enhance primary cervical cancer prevention efforts.

The HPV-16/18 AS04-adjuvanted vaccine (Cervarix, GlaxoSmithKline Biologicals) and HPV-6/11/16/18 vaccine (Gardasil, Merck) consist of virus-like particles (VLPs) composed of relatively well conserved L1 capsid proteins. The neutralising antigenic sites (epitopes) defined so far are mainly situated on one of five variable loops of the L1 capsomer. These are exposed on virion surfaces and should be readily accessible to neutralising antibodies.6, 7, 8 In theory, aminoacid sequence or conformational differences determine the type-specificity of any HPV-neutralising epitope. Some oncogenic HPV types that are phylogenetically related to vaccine types presumably share epitopes that can elicit cross-reactive immune responses, although cross-neutralising antibodies might be induced by HPV vaccination at much lower levels than type-specific antibodies.9

This report summarises cross-protection data with the HPV-16/18 vaccine in the end-of-study analysis of the PApilloma TRIal against Cancer In young Adults (PATRICIA). In general, cervical intraepithelial neoplasia grade 2 or greater (CIN2+) is the accepted clinical endpoint to evaluate HPV vaccine efficacy. However, analyses can be biased if a lesion is co-infected with both a vaccine and a non-vaccine oncogenic HPV type, since definitive causality to a single HPV type cannot be readily assigned.10, 11, 12 This confounding bias particularly applies to analyses of cross-protection, because HPV-16 and HPV-18 are common co-infections and are more prevalent than other HPV types in cervical lesions. Additionally, as a result of vaccination, HPV-16 and HPV-18 infections are differentially removed from the vaccine and control groups. To overcome these biases, we did analyses of CIN2+ and the more stringent endpoint, CIN3+, which either include or exclude cases co-infected with a vaccine type. We also did complementary analyses using virological endpoints. Persistent HPV infection usually precedes cervical cancer and its precursor lesions (CIN grade 2 and 3),13, 14, 15, 16 and therefore provides a relevant marker for the risk of developing these precancerous lesions.

To estimate the extent of cross-protection, we did the analyses in various cohorts: the according-to-protocol cohort for efficacy (ATP-E), the total vaccinated HPV-naive cohort (TVC-naive), and the total vaccinated cohort (TVC). The ATP-E cohort represents a population of women who at baseline had no evidence of infection with the HPV type under analysis and who received all three vaccine doses. In terms of exposure to and acquisition of HPV types, the TVC-naive approximates the current primary target of HPV vaccination programmes. The TVC includes women with evidence of current or previous infection with oncogenic HPV types, and approximates a population currently targeted by catch-up HPV vaccination programmes. Data regarding other measures of efficacy in the TVC-naive and TVC are reported in an accompanying article by Lehtinen and colleagues.17

Section snippets

Methods

The trial methods have been previously described in detail, and the results of event-driven analyses presented.10, 11 In this end-of-study analysis after 48 months of follow-up, we report vaccine efficacy against types other than HPV-16 and HPV-18, using persistent infection, CIN2+, and CIN3+ as endpoints.

Results

A total of 16 114, 11 644, and 18 644 women were included in the ATP-E (vaccine n=8067, control n=8047), TVC-naive (vaccine n=5824, control n=5820), and TVC cohorts (vaccine n=9319, control n=9325), respectively. Compliance was high. Roughly 16% of participants (3034 of 18 644) were lost to follow-up by the end of the study; the number of participants who did not complete the study was balanced between the vaccine and control groups.17 In the ATP-E cohort, mean and median follow-up times after

Discussion

Data from the end-of-study analysis of PATRICIA show that the HPV-16/18 vaccine provides cross-protective efficacy against 6-month persistent infection and CIN2+ associated with HPV-33, HPV-31, HPV-45, and HPV-51. Consistent vaccine efficacy for all endpoints across all cohorts was seen only for HPV-33. As expected, estimates of vaccine efficacy were generally higher in the TVC-naive and ATP-E cohorts than in the TVC. The TVC-naive and ATP-E cohorts represent the primary target population for

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    For the HPV PATRICIA Study Group see webappendix p 9

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